Objective: To explore the relationship between neuronal nitrie oxide synthase (nNOS) molecule and antidepressant-like effects of fluoxetine. Methods:The antidepressant activity was assessed in forced swimming test (FST) and tail suspension test (TST) behavioral paradigm. Total immobility time was registered during the period of 5 or 6 min. ICR mice were treated with fluoxetine or pretreated with L-arginine/D-arginine,and wildtype(WT) mice and mice lacking nNOS gene[knock-out (KO)]were treated with fluoxetine,and then the immobility time in the FST and TST was analyzed. Results: In ICR mice,the immobility time in the FST and TST as reduced by fluoxetine treatment,and the antidepressant-like effect of fluoxetine in the FST and TST was prevented by the pretreatment with L-arginine,but not D-arginine. In WT mice,administrations of fluoxetine caused antidepressant-like effect in the FST,whereas in KO mice fluoxetine was ineffective. Conclusion: nNOS molecule is required by antidepressant-like effect of fluoxetine.